TY - JOUR
T1 - Zfta–rela dictates oncogenic transcriptional programs to drive aggressive supratentorial ependymoma
AU - Arabzade, Amir
AU - Zhao, Yanhua
AU - Varadharajan, Srinidhi
AU - Chen, Hsiao Chi
AU - Jessa, Selin
AU - Rivas, Bryan
AU - Stuckert, Austin J.
AU - Solis, Minerva
AU - Kardian, Alisha
AU - Tlais, Dana
AU - Golbourn, Brian J.
AU - Stanton, Ann Catherine J.
AU - Chan, Yuen San
AU - Olson, Calla
AU - Karlin, Kristen L.
AU - Kong, Kathleen
AU - Kupp, Robert
AU - Hu, Baoli
AU - Injac, Sarah G.
AU - Ngo, Madeline
AU - Wang, Peter R.
AU - De León, Luz A.
AU - Sahm, Felix
AU - Kawauchi, Daisuke
AU - Pfister, Stefan M.
AU - Lin, Charles Y.
AU - Hodges, H. Courtney
AU - Singh, Irtisha
AU - Westbrook, Thomas F.
AU - Chintagumpala, Murali M.
AU - Blaney, Susan M.
AU - Parsons, Donald W.
AU - Pajtler, Kristian W.
AU - Agnihotri, Sameer
AU - Gilbertson, Richard J.
AU - Yi, Joanna
AU - Jabado, Nada
AU - Kleinman, Claudia L.
AU - Bertrand, Kelsey C.
AU - Deneen, Benjamin
AU - Mack, Stephen C.
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/9
Y1 - 2021/9
N2 - More than 60% of supratentorial ependymomas harbor a ZFTA–RELA (ZRfus ) gene fusion (formerly C11orf95–RELA). To study the biology of ZRfus, we devel-oped an autochthonous mouse tumor model using in utero electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE-driven ZRfus tumors by CUT&RUN, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing and compared with human ZRfus-driven ependymoma. In addition to direct canonical NFκB pathway activation, ZRfus dictates a neoplastic transcriptional program and binds to thousands of unique sites across the genome that are enriched with Plagl family transcription factor (TF) motifs. ZRfus activates gene expression programs through recruitment of transcriptional coactivators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZRfus target genes converge on developmental programs marked by Plagl TF proteins, and activate neoplastic programs enriched in Mapk, focal adhesion, and gene imprinting networks.
AB - More than 60% of supratentorial ependymomas harbor a ZFTA–RELA (ZRfus ) gene fusion (formerly C11orf95–RELA). To study the biology of ZRfus, we devel-oped an autochthonous mouse tumor model using in utero electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE-driven ZRfus tumors by CUT&RUN, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing and compared with human ZRfus-driven ependymoma. In addition to direct canonical NFκB pathway activation, ZRfus dictates a neoplastic transcriptional program and binds to thousands of unique sites across the genome that are enriched with Plagl family transcription factor (TF) motifs. ZRfus activates gene expression programs through recruitment of transcriptional coactivators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZRfus target genes converge on developmental programs marked by Plagl TF proteins, and activate neoplastic programs enriched in Mapk, focal adhesion, and gene imprinting networks.
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U2 - 10.1158/2159-8290.CD-20-1066
DO - 10.1158/2159-8290.CD-20-1066
M3 - Article
C2 - 33741710
AN - SCOPUS:85106672207
SN - 2159-8274
VL - 11
SP - 2200
EP - 2215
JO - Cancer Discovery
JF - Cancer Discovery
IS - 9
ER -